Excipient Material properties

It may sometimes by necessary to supplement the properties of the drug so that it compresses more easily, and these needs have been realized by several manufacturers of excipients. Materials described as compression aids are now commercially available. Ideally, such adjuvants should develop mechanical strength while improving, or at least not adversely affecting, release characteristics. Among the most successful at meeting both these needs have been the microcrystalline celluloses (partially acid-hydrolyzed forms of cellulose). A number of grades are available based upon particle size and distribution. 

One way to eliminate potential scale-up problems is to develop formulations that are very robust with respect to processing conditions. A comprehensive database of excipients detailing their material properties may be indispensable for this purpose. However, in practical terms, this cannot be achieved without some means of testing in production environment and, since the initial drug substance is usually available in small quantities, some form of simulation is required on a small scale. 

The authors determined the mechanical properties of the excipients in this manuscript at or near 0.85 SF except for dicalcium phosphate (DCP). The low SF that could be achieved with DCP ( 0.6) demonstrates that its compressibility was less than the compressibility of the other materials and that relevant comparisons to them could not be easily made. When the SF difference between materials is 0.03 or less, property differences due to SF are normally relatively small and comparisons can be made with confidence, but when the SF difference is greater than 0.03, a meaningful material comparison becomes more difficult to achieve. In that situation, material comparisons using only general qualitative statements are appropriate. The latter scenario was the case with DCP, and this has been discussed in the section Calcium Phosphate Dibasic. In the discussions that follow, excipient mechanical properties were determined at a SF of 0.85 unless otherwise noted. 

All three grades of mannitol showed similar, relatively low BFI values. This low tendency for brittle fracture represents a very significant advantage of mannitol, particularly with direct compression formulations where material properties, and not powder processing, must be used alone to overcome deficiencies of the API and other ingredients. It should be remembered that low BFI is but one consideration of many when selecting excipients for direct compression formulations. 

However, some excipients have multiple functions. For example, microcrystalline cellulose can function as a filler, a binder, and a disintegrant. As seen in Table 7.3, a typical low-dose formulation could include more than 85% filler—binders. Thus, physical and chemical properties for these specialty excipients are extremely important in a low-dose formulation for manufacturability, product performance, and longterm stability. Because the poor physicomechanical properties of components are not altered during manufacture as they are in the wet or dry granulation process, critical material properties and their impact on product quality attributes should be well characterized and understood.23 Discussion in this section will focus on fillers-binders. For those requiring more information on excipients, several excellent books and review articles are available in the literature.24-27... 

TABLE 9.5 Analytical Techniques Used to Characterize Physical and Material Properties of Excipients... 

Instability attributable to excipient-mediated water distribution in solids and powders has been explained by excipient physical properties. " Crystalline materials will not uptake moisture until the deliquescent point is reached. In contrast, amorphous excipients will absorb water until their glass transition temperatures fall below the ambient temperature when the mobility of the molecules has increased so much that excipient crystallization will occur to expel the absorbed water from the crystal lattice. Before crystal-... 

By determining these indices for drugs and excipients a portfolio of material properties can be assembled, and by using these indices, excipients can be rationally chosen to overcome an undesirable characteristic of the API. In other words the indices of the individual components and the final formulation can be u.sed to assess the mechanical properties thus, providing an important tool to predicting the quality of the final formulation. 

The Purdue Ontology for Pharmaceutical Engineering (POPE) was developed with its component ontologies for descriptions of materials, chemical stractures, reactions, material properties and experiments. Based on POPE an excipient interaction prediction/diagnosis apphcation which made use of stmctural and environmental information was presented. There are several challenges in the horizon, which include the consideration of rates of reaction to determine relevance and evaluation of multiple measures of molecular similarity. 

A number of excipients contain additives that serve as stabilizers or to improve material properties. Stabilizers can themselves affect drug stability,... 

The series mission was expanded some time ago to include profiles of excipient materials, reflecting that these materials require the full degree of scrutiny historically associated with drug compounds. These highly detailed compilations of excipient properties and analytical methods have been well received by workers in the field, and such profiles will continue to be sought. In the present volume, the series mission is further expanded to include a profile of a natural product which has been used as a precursor material in the synthesis of new drug candidates. If this information proves to be of interest to the pharmaceutical community, additional chapters of this type will be developed. 

To reiterate a common theme, characterization of the crystalline form selected should be extensive in order to assure a sound scientific understanding of the material properties of the substance is in hand during the development process. An appreciation of the chemical and physical compatibility of the solid form with the excipients to be used in the final formulation is required. Often called excipient compatibility screening. 

The importance of using sphere-forming excipients was noted early on. Conine and Hadley dted the necessity of using microcrystalline cellulose (4). Reynolds went on to indicate the need for either adhesive or capillary type binders (5). He dted cellulose gums, natural gums, and synthetic polymers as adhesives and microcrystalline cellulose, talc, and kaolin as capillary type binders. Since then much work has been conducted in an attempt to understand the significance of material properties. Some of the studies are discussed in the following text. 

The main focus of this chapter is to examine the critical material properties that influence polymeric binder and filler-binder performance of directly compressible excipients, and how these material properties can be optimized and integrated with other functionalities via particle engineering. 

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